ORCID Profile
0000-0002-4722-6897
Current Organisation
University of Newcastle Australia
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Biological psychology not elsewhere classified | Central nervous system | Neurosciences
Publisher: Wiley
Date: 30-04-2021
DOI: 10.1002/PRP2.767
Abstract: Alcohol use disorder (AUD) and meth hetamine use disorder (MUD) are prevalent and have high adverse impacts on both the in idual and society. Current treatment strategies for these disorders are ineffective at a population level. Lorcaserin, a 5‐HT 2C receptor agonist, has shown potential at reducing the symptoms of substance use disorder. This pilot study (initiated prior to market withdrawal) examined feasibility and safety of lorcaserin treatment in people undergoing residential detoxification and treatment for AUD and MUD. This was an open label pilot study of lorcaserin where participants ( n = 10 AUD n = 8 MUD) received 10‐mg lorcaserin daily for 4 days then twice daily for 1 month. Primary outcome measures included recruitment and retention rate, incidence of treatment‐emergent events, incidence of meth hetamine or alcohol withdrawal‐related events, heart rate, and blood pressure. Secondary measures included pharmacokinetic data and self‐reported alcohol or meth hetamine use, craving, and psychological distress. AUD participants were recruited faster and had a greater retention rate compared with MUD participants. Lorcaserin did not alter vital signs, was well tolerated, and had a similar pharmacokinetic profile to in iduals with obesity. Lorcaserin reduced self‐reported alcohol and hetamine‐type substance use and craving in AUD and MUD participants, respectively. Self‐reported psychological health also improved over the treatment period for all participants. Despite the pilot nature of this study, our data support the notion of 5‐HT 2C receptors as a therapeutic target for drug and alcohol abuse.
Publisher: Wiley
Date: 27-10-2021
DOI: 10.1111/JNC.15208
Publisher: Society for Neuroscience
Date: 16-03-2016
DOI: 10.1523/JNEUROSCI.4299-15.2016
Abstract: In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub→NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory κ opioid-receptor based DREADD (KORD) in vSub→NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context-induced relapse after punishment-imposed abstinence and further suggest a role of the vSub→NAc projection in this relapse. SIGNIFICANCE STATEMENT In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Public Library of Science (PLoS)
Date: 30-05-2014
Publisher: SAGE Publications
Date: 16-10-2020
Abstract: The lateral hypothalamic orexin (hypocretin) system has a well-established role in the motivation for reward. This has particular relevance to substance use disorders since orexin-1 receptors play a critical role in alcohol-seeking behavior, acting at multiple nodes in relapse-associated networks. This study aimed to further our understanding of the role of orexin-1 receptor signaling within the lateral hypothalamus and bed nucleus of the stria terminalis, specifically in context-induced relapse to alcohol-seeking following punishment-imposed abstinence. We trained inbred male alcohol-preferring rats to self-administer alcohol in one environment or context (Context A) and subsequently punished their alcohol-reinforced lever presses in a different environment (Context B) using contingent foot shock punishment. Finally, we tested rats for relapse-like behavior in either context following systemic, intra-lateral hypothalamus or intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism with SB-334867. We found that systemic orexin-1 receptor antagonism significantly reduced alcohol-seeking in both contexts. Intra-lateral hypothalamus orexin-1 receptor antagonism significantly reduced alcohol-seeking in Context A whereas intra-bed nucleus of the stria terminalis orexin-1 receptor antagonism had no effect on alcohol-seeking behavior. Our results suggest a role for the orexin-1 receptor system in context-induced relapse to alcohol-seeking. Specifically, intra-lateral hypothalamus orexin microcircuits contribute to alcohol-seeking.
Publisher: Wiley
Date: 15-02-2018
DOI: 10.1002/PRP2.384
Publisher: American Psychological Association (APA)
Date: 04-2017
DOI: 10.1037/BNE0000185
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.PHYSBEH.2019.112638
Abstract: Environmental enrichment during periods of abstinence can reduce the risk of relapse to drug-seeking behavior. We trained rats to self-administer alcohol in one environment (Context A), then punished their alcohol-reinforced lever responses in a different environment using contingent foot shock (Context B). Rats were then kept in forced abstinence in either standard housing or environmental enrichment conditions for 31 days. The following day, we examined alcohol seeking behavior. We found a significant reduction in alcohol seeking behavior in Context A after environmental enrichment. Our results suggest that environmental enrichment can reduce alcohol seeking behavior following a period of abstinence.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2018
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.YFRNE.2018.09.002
Abstract: The neuropeptide oxytocin has been associated with food intake and feeding behaviour. This systematic review aimed to investigate the impact of oxytocin on dietary intake and feeding behaviour in rodent studies. Six electronic databases were searched to identify published studies to April 2018. Preclinical studies in mice and rats were included if they reported: (1) a dietary measure (i.e. food or nutrient and/or behaviour (2) an oxytocin measure, and (3) relationship between the two measures. A total of 75 articles (n = 246 experiments) were included, and study quality appraised. The majority of studies were carried out in males (87%). The top three oxytocin outcomes assessed were: exogenous oxytocin administration (n = 126), oxytocin-receptor antagonist administration (n = 46) and oxytocin gene deletion (n = 29). Meta-analysis of exogenous studies in mice (3 studies, n = 43 comparisons) and rats (n = 8 studies, n = 82 comparisons) showed an overall decrease in food intake with maximum effect shown at 2 h post-administration.
Publisher: American Psychological Association (APA)
Date: 12-2021
DOI: 10.1037/BNE0000486
Abstract: Persistent alcohol use despite negative consequences is a key feature of alcohol use disorder (AUD) and is typically assessed using punishment in animal models. This study examined relapse-like behavior in male and female alcohol-preferring iP rats following punishment-imposed voluntary abstinence to alcohol seeking. We focused on alcohol seeking in the punishment-associated environment after prolonged abstinence. Finally, we sought to understand the predictability of relapse-like behavior by examining AUD comorbidities, namely, anxiety-like behavior and the response to repeated, moderate punishment. We found no sex differences in operant self-administration of alcohol. However, we did find a reduced propensity to relapse in the punishment-associated environment in female rats following prolonged abstinence. Relapse propensity was associated with the response to punishment during operant training, but not prior anxiety-like behavior. Together these results highlight the importance of studying sex differences in relapse to alcohol seeking. In addition, the behavioral response to a negative consequence may be a predictor of relapse, particularly in females. Improving our understanding of the sexually dimorphic responses in alcohol seeking may be a powerful tool for designing personalized, or at least sex-specific, approaches to treatment and rehabilitation programs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Publisher: Wiley
Date: 23-10-2020
DOI: 10.1111/GBB.12613
Abstract: Overeating is a major contributing factor to obesity and related health complications. For women, in particular, negative emotions such as stress strongly influence eating behavior and bingeing episodes. Modeling this type of binge eating in rodents presents challenges: firstly, stress-induced anorexia is commonly observed in rodents therefore a mild stressor is required in order to observe an orexigenic effect. Second, many studies report using calorie restriction to observe the required behavior yet this does not necessarily reflect the human condition. Thus, the aim of this study was to develop a model of emotional stress-induced bingeing independent of caloric restriction. Female and male C57BL/6J mice were ided into ad libitum (n = 20 per sex) and food-restricted (n = 20 per sex) groups which were both further split into a control group and a group exposed to frustration stress (n = 10 per group). All mice were provided intermittent access to a highly palatable food in 2 cycles. At the end of each cycle the stress group was subjected to a 15-minute frustration episode where highly palatable food was within the home cage but inaccessible. Both groups were then given free access for 15 minutes. Frustrated female mice from the ad libitum displayed binge-like behavior compared with controls (P = .0001). Notably, this behavior was absent in males. Ovariectomy had no impact on binge-like behavior. Collectively, these data validate a novel model of emotional stress-induced binge eating specific to female mice which does not require caloric restriction and is not driven by ovarian hormones.
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2023
DOI: 10.1101/2023.02.03.527084
Abstract: Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN PVN CRH ), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another, mostly unexplored hypothesis is that the direct activity of PVN CRH neurons and their input to other stress- and reward-related brain regions drives these behaviours. To further understand the direct involvement of PVN CRH neurons in motivation, we used optogenetic stimulation to activate these neurons one hour/day for 5 consecutive days and showed increased acute stress-related behaviours and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVN CRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVN CRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioural changes may, in part, be driven by PVN CRH synaptic projections to the LH.
Publisher: Springer Science and Business Media LLC
Date: 25-03-2018
DOI: 10.1007/S00213-018-4887-7
Abstract: Alcohol use disorder is a complex syndrome with multiple treatment points including drug-induced pathology, withdrawal management, behavioral/cognitive strategies, and relapse prevention. These different components may be complicated by genotype and phenotype. A huge milestone for the treatment of alcohol use disorder across several countries in the last 10 years was the introduction of practice guidelines integrating clinical expertise and research evidence. These provide a summary of interventions that have been shown to be effective following rigorous and replicated clinical trials. Inspection of these guidelines reveals good consistency, but little evidence of progress in treatment approaches for alcohol use disorder over the past decade. In this mini-review, we discuss emerging treatments for alcohol use disorder that may supplement or improve the evidence-based treatments that are currently recommended. New medications, the emergence of digital technology, and other novel approaches such as transcranial magnetic stimulation are all discussed with reference to treatments already in practice. We also consider how in idual differences in genotype and phenotype may affect outcomes. Together with improvements in technology, this knowledge offers a powerful tool for designing personalized approaches to treatment, and hence improving prognosis for rehabilitation programs.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2023
DOI: 10.1038/S41386-023-01665-6
Abstract: It is well-established that stress and negative affect trigger eating disorder symptoms and that the brains of men and women respond to stress in different ways. Indeed, women suffer disproportionately from emotional or stress-related eating, as well as associated eating disorders such as binge eating disorder. Nevertheless, our understanding of the precise neural circuits driving this maladaptive eating behavior, particularly in women, remains limited. We recently established a clinically relevant model of ‘emotional’ stress-induced binge eating whereby only female mice display binge eating in response to an acute “emotional” stressor. Here, we combined neuroanatomic, transgenic, immunohistochemical and pathway-specific chemogenetic approaches to investigate whole brain functional architecture associated with stress-induced binge eating in females, focusing on the role of Vglut2 projections from the paraventricular thalamus (PVT Vglut2+ ) to the medial insular cortex in this behavior. Whole brain activation mapping and hierarchical clustering of Euclidean distances revealed distinct patterns of coactivation unique to stress-induced binge eating. At a pathway-specific level, PVT Vglut2+ cells projecting to the medial insular cortex were specifically activated in response to stress-induced binge eating. Subsequent chemogenetic inhibition of this pathway suppressed stress-induced binge eating. We have identified a distinct PVT Vglut2+ to insular cortex projection as a key driver of “emotional” stress-induced binge eating in female mice, highlighting a novel circuit underpinning this sex-specific behavior.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.NEUROPHARM.2018.09.037
Abstract: Corticotropin releasing factor (CRF) is a key component of stress responsivity, modulating related behaviors including anxiety and reward. Difficulties identifying CRF neurons, using traditional approaches including immunohistochemistry, has led to the development of a number of transgenic CRF reporter mice. The Crh-IRES-Cre::Ai14 (tdTomato) reporter mouse is increasing in popularity as a useful tool to assess the localization, connectivity and function of CRF neurons in various stress-related behaviors. However, without proper characterization of reporter expression, the in vivo and in vitro manifestations resulting from the manipulation of these cells must be interpreted with caution. Here we mapped the distribution of tdTomato-expressing CRF cells throughout the rostro-caudal extent of the Crh-IRES-Cre::Ai14 mouse brain. To determine if reporter expression faithfully reproduced native CRF expression, we assessed the colocalization of CRF expression with tdTomato reporter expression across several brain regions. Good concordance was observed in the extended amygdala and paraventricular nucleus of the hypothalamus (PVN), while discrepancies were observed within the lateral hypothalamus and hippoc us. Finally, we examined the activation of CRF neurons in Crh-IRES-Cre::Ai14 mice in response to different types of stressors using Fos immunohistochemistry. Acute psychological (swim) and pharmacological (yohimbine) stress stimulated Fos-protein expression in PVN CRF neurons. Interestingly though, exposure to four daily restraint stress sessions followed by a novel acute stressor did not further recruit CRF neurons across any brain region examined. Our results highlight the importance of thoroughly characterizing reporter mice before use and suggest that acute versus repeated stress may differentially impact the CRF system. This article is part of the Special Issue entitled 'Hypothalamic Control of Homeostasis'.
Publisher: Wiley
Date: 27-12-2021
DOI: 10.1002/PRP2.907
Abstract: Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M 4 and M 5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M 1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M 1 mAChRs in alcohol consumption, we tested operant self‐administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3‐4) schedules. Enhancing M 1 mAChR signaling (via the M 1 PAM‐Agonist PF‐06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M 1 enhancement on natural reward (sucrose) self‐administration. Systemic administration of PF‐06767832 (1 mg/kg, i.p.) also reduced operant sucrose self‐administration, suggesting the actions of the M 1 receptor may be non‐selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M 1 enhancement via systemic PF‐06767832 administration reduced food and water consumption. Together our results suggest the M 1 PAM‐agonist, PF‐06767832, non‐specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M 1 agonists, PAMs, and PAM‐agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/7854_2016_56
Abstract: Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct projections to the hypophysiotropic neurons that coordinate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Consequently, hyperactivity of the orexin system is associated with increased motivated arousal and anxiety, and is emerging as a key feature of panic disorder. Accordingly, there has been significant interest in the therapeutic potential of pharmacological agents that antagonize orexin signaling at their receptors for the treatment of anxiety disorders. In contrast, disorders characterized by inappropriately low levels of motivated arousal, such as depression, generally appear to be associated with hypoactivity of the orexin system. This includes narcolepsy with cataplexy, a disorder characterized by the progressive loss of orexin neurons and increased rates of moderate/severe depression symptomology. Here, we provide a comprehensive overview of both clinical and preclinical evidence highlighting the role of orexin signaling in stress reactivity, as well as how perturbations to this system can result in dysregulated behavioral phenotypes.
Publisher: Wiley
Date: 10-02-2021
DOI: 10.1111/JNC.15310
Abstract: Understanding brain structures and circuits impacted by alcohol use disorder is critical for improving our future prevention techniques and treatment options. A brain region that has recently gained traction for its involvement in substance use disorder is the insular cortex. This brain region is multi‐functional and spatially complex, resulting in a relative lack of understanding of the involvement of the insular cortex in alcohol use disorder. Here we discuss the role of the insular cortex in alcohol use disorder, particularly during periods of abstinence and in response to alcohol and alcohol‐related cues and contexts. We also discuss a broader role of the insular in alcohol‐associated risky decision making and impulse control. Finally, we canvas potential challenges associated with targeting the insular cortex to treat in iduals with alcohol use disorder. image
Publisher: Frontiers Media SA
Date: 10-03-2015
Publisher: Wiley
Date: 22-09-2017
DOI: 10.1111/EJN.13674
Abstract: Altered motivated behaviour is a cardinal feature of several neuropsychiatric conditions including mood disorders. One well-characterized antecedent to the development of mood disorders is exposure to early life stress (ELS). A key brain substrate controlling motivated behaviour is the lateral hypothalamus (LH). Here, we examined the effect of ELS on LH activation and the motivation to self-administer sucrose. We tested whether chemogenetic activation of LH circuits could modify sucrose responding in ELS rats and examined the impact on LH cell populations. Male rat pups were maternally separated for 0 or 3 h on postnatal days 2-14. During adolescence, rats received bilateral injections of hM3D(Gq), the excitatory designer receptor exclusively activated by designer drugs, into LH. In adulthood, rats were trained to self-administer sucrose and tested under a progressive ratio schedule to determine their motivation for reward following injection with either vehicle or 5 mg/kg clozapine-N-oxide. Brains were processed for Fos-protein immunohistochemistry. ELS significantly suppressed lever responding for sucrose, indicating a long-lasting impact of ELS on motivation circuits. hM3D(Gq) activation of LH increased responding, normalizing deficits in ELS rats, and increased Fos-positive orexin and MCH cell numbers within LH. Our findings indicate that despite being susceptible to environmental stressors, LH circuits retain the capacity to overcome ELS-induced deficits in motivated behaviour.
Publisher: Frontiers Media SA
Date: 23-07-2014
Publisher: Society for Neuroscience
Date: 03-12-2018
DOI: 10.1523/JNEUROSCI.1596-18.2018
Abstract: Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABA A and GABA B receptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial in idual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI. SIGNIFICANCE STATEMENT A key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the “adverse consequence” environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.
Publisher: Frontiers Media SA
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 21-08-2020
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.BRAINRES.2018.08.005
Abstract: There are currently 3 FDA approved treatments for alcohol use disorder (AUD) in the USA, opioid receptor antagonists such as naltrexone, disulfiram and ac rosate. To date, these have been largely inadequate at preventing relapse at a population level and this may be because they only target certain aspects of AUD. Recently, suvorexant, a dual orexin receptor antagonist, has been FDA approved for the treatment of insomnia. Importantly, sleep disruptions occur during both acute and prolonged alcohol exposure and sleep deprivation is a potent factor promoting relapse to alcohol use. In this mini review article, we explore the therapeutic potential of suvorexant for the treatment of AUD. In particular, we highlight that in addition to altering the motivational properties of alcohol, suvorexant may also address key physiological components associated with alcohol withdrawal and abstinence, such as sleep disruptions, which should in turn help reduce or prevent relapse.
Publisher: Elsevier BV
Date: 07-2017
Publisher: Wiley
Date: 26-02-2018
DOI: 10.1111/BPH.14146
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.BRAINRES.2019.146597
Abstract: Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population level. One reason for this may be that current pharmacotherapeutics focus on the reward pathway in relapse prevention, rather than addressing AUD from a holistic perspective. Importantly, one often overlooked symptom of AUD is sleep disruption. In recent years, an efficient, relatively low risk and economic strategy that has proven successful in other disorders is the repositioning or repurposing of drugs approved for the treatment of other indications. Suvorexant, a dual orexin receptor antagonist, has been licensed for the treatment of insomnia in the USA, Australia and Japan. The orexin system also plays a role in the emotional dysregulation that occurs during withdrawal from alcohol use and in alcohol-seeking behaviours. These two factors prompted the planning of a clinical trial into the use of suvorexant to treat insomnia in alcohol dependent in iduals during and 24 weeks post-acute alcohol withdrawal. In this review we outline the comorbid nature of AUD and sleep disruptions. We then highlight the role of the orexin system in both sleep-wake regulation and AUD. Finally, we discuss our plan for a Phase II double blind placebo controlled trial examining the effectiveness of suvorexant for the treatment of comorbid insomnia and AUD.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.NEURON.2018.03.033
Abstract: Contexts exert bi-directional control over relapse to drug seeking. Contexts associated with drug self-administration promote relapse, whereas contexts associated with the absence of self-administration protect against relapse. The nucleus accumbens shell (AcbSh) is a key brain region determining these roles of context. However, the specific cell types, and projections, by which AcbSh serves these dual roles are unknown. Here, we show that contextual control over relapse and abstinence is embedded within distinct output circuits of dopamine 1 receptor (Drd1) expressing AcbSh neurons. We report anatomical and functional segregation of Drd1 AcbSh output pathways during context-induced reinstatement and extinction of alcohol seeking. The AcbSh→ventral tegmental area (VTA) pathway promotes relapse via projections to VTA Gad1 neurons. The AcbSh→lateral hypothalamus (LH) pathway promotes extinction via projections to LH Gad1 neurons. Targeting these opposing AcbSh circuit contributions may reduce propensity to relapse to, and promote abstinence from, drug use.
Location: Australia
Start Date: 11-2023
End Date: 12-2026
Amount: $393,903.00
Funder: Australian Research Council
View Funded Activity